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Home , Epidemic typhus, Queensland tick typhus, Rickettsia, Rickettsia australis

Update on Australian Rickettsial Infections

Stephen Graves Founder & Medical Director Australian Rickettsial Reference Laboratory Geelong, Victoria & Newcastle NSW.

Director of Microbiology Pathology North – Hunter NSW Health Pathology Newcastle. NSW

Conjoint Professor, University of Newcastle, NSW

What are rickettsiae?

• • Rod-shaped (0.4 x 1.5µm) • Gram negative • Obligate intracellular growth • Energy parasite of host cell • Invertebrate vertebrate through life stages • invertebrate via • Larva invertebrate bite/faeces (larva “chigger”, nymph, adult ♀) • Nymph • Adult (♀♂)

Classification of Rickettsiae (phylum) α- () 1. – Group Group 2. – 3. (not in Australia?) 4. (veterinary only in Australia?) 5. (? Koalas)

NB: () is a γ-proteobacterium NOT a true rickettsia despite being -transmitted (not covered in this presentation)

1 Rickettsiae from Australian Patients

Rickettsia Vertebrate Invertebrate (human disease) Host Host A. Spotted Fever Group Rickettsia i. Native rats (, () Bandicoots I. tasmani) ii. R. honei Native reptiles (blue-tongue Tick (Bothriocroton (Flinders Island Spotted Fever) lizard & snakes) hydrosauri) iii.R. honei sub sp. Unknown Tick (Haemophysalis marmionii novaeguineae) (Australian Spotted Fever) iv.R. gravesii Macropods Tick (Amblyomma (? Human ) (kangaroo, wallabies) triguttatum) Feral pigs (WA) v. R. felis cats/dogs (cat flea typhus) (Ctenocephalides felis) All these rickettsiae grown in pure culture

Rickettsiae in Australian patients (cont.)

Rickettsia Vertebrate Invertebrate Host Host B. Typhus Group Rickettsia R. typhi Rodents (rats, mice) () (Ctenocephalides felis)

(R. prowazekii) (humans)* (human body ) ╪ ( typhus) (Brill’s disease) C. Scrub Typhus Rickettsia Orientia tsutsugumushi Bandicoots, various native (various antigenic forms) rodents (larval stage only “chiggers”) Rattus spp. (Leptotrombidium deliense) Melomys spp. Uromys spp. * Migrants from endemic countries; returned soldiers after WWI ╪ not in Australia?

Rickettsiae from Australian animals 1. Dog cyclic thrombocytopaenia. Tx by brown dog tick, Rhipicephalus sanguineous (outback Australia) 2. Anaplasma marginale Cattle tick fever (~ 10% cases)* Rhipicephalus (Boophilus) micropus (endemic in northern Australia) 3. Dogs may be bacteraemic but asymptomatic (~ 9% prevalence in Brisbane) ? Reservoirs for flea infection. 4. No Ehrlichia canis in Australian dogs * 90% cases caused by Babesia spp.

2 Rickettsia present in Australian animals but unlikely to be human

Rickettsia Vertebrate Invertebrate (Spotted Fever Group) Host Host

R. antechini Antechinus (? Tick Ixodes antechini) ╪ ( mouse) (WA)

R. argasii Microbat (VIC) Bat tick (Argus dewae) ╪

Both rickettsiae in pure culture ╪ these ticks do not bite humans

Rickettsiae present in Australia as identified only (not yet isolated nor grown in pure culture)

Rickettsia Vertebrate Invertebrate Host Host (ticks) 1. R. tasmanensis Tasmanian Devil (TAS) Ixodes tasmani R. massiliae – like 2. R. massiliae – like Koala (VIC & NSW) I. tasmani (Koala genotype) Rickettsiella sp. 3. R. bellii – like Echidna (VIC) Bothriocroton concolor

4. R. massiliae – like Wombat (VIC) B. auruginans

5. R. tamurae – like Reptiles (NT) Ambloyomma • Yellow-spotted monitor fimbriatum • Water python • Green tree snake

Clinical presentation of rickettsial disease in Australian patients

Not a lot of difference between the different rickettsiae in presenting symptoms • Fever • Rash (macular, papular, vesicular) • Eschar (following tick or bite) • Myalgia • Headache • Acute fatigue chronic fatigue (“post-infectious fatigue”) Severity and duration of illness varies significantly

3 Laboratory findings in rickettsial disease in Australian patients.

• Blood film often normal ( “viral”) Polymorphs Lymphocytes Platelets • Liver function tests (transaminitis) • Na • CRP (>100)

Specific investigations for diagnosis of rickettsial infection 1. Doctor must think of rickettsia as part of differential diagnosis. 2. Early in infection (day 1 – 5) i. PCR Assays can differentiate • Spotted Fever Group/Typhus Group rickettsiae from • Scrub typhus Group rickettsiae If sufficient DNA available it may be possible to sequence rickettsia specific genes (e.g. omp A, omp B, citrate synthase) and compare them with sequences of known rickettsiae and thus definitively identify the rickettsia. Samples: • Eschar swab (+++) • Eschar biopsy (+++) • Blood (EDTA) (+) (bacteraemia transient)

Specific investigations for diagnosis of rickettsial infection (cont.) ii. Culture Research technique, only done in reference laboratories. Slow, difficult Requires culture facilities (e.g. VERO, DH82) Sample: • blood (EDTA) • Eschar biopsy

4 Specific investigations for diagnosis of rickettsial infection (cont.)

Later in infection (> day 6) iii. Serology – main laboratory diagnostic modality “microimmunofluorescence” is gold-standard assay type. Spotted Fever Group antigens used in ARRL. R. australis (Queensland Tick Typhus) R. honei (Flinders Island Spotted Fever) R. conorii (Mediterranean Spotted Fever) R. africae () R. rickettsii (Rocky Mountain Spotted Fever) R. felis (cat flea typhus/ Flea-borne Spotted Fever)

Specific investigations for diagnosis of rickettsial infection III. Serology (cont.) Typhus Group R typhi (murine typhus) R. prowazekii () ╪

Scrub Typhus Group O. chuto (new ).

╪ For refuges from endemic countries (reactivation, Brill’s disease).

Microimmunofluorescence serology for diagnosis of rickettsial infection Patient sera is screened at 1:128 dilution. If negative, reported (negative: titre < 1:128) If positive, titration done: 1/128 1/256 1/512 1/1024 (if + reported as “titre ≥ 1:1024”)*

• * If comparing two strongly positive sera from the same patient it is necessary to titrate both sera to end-point to look for changing titres. • If laboratory has earlier serum please advise them of this on pathology request form and ask the laboratory to titrate both sera together (“in parallel”). This reduces run to run variability in the IF assay and will demonstrate genuine changes in antibody titres if present (e.g. 1:1024  1:4096) or not (e.g. 1:1024  1:1024)

5 Treatment

Doxycycline 100mg o q12hr 7 days or Azithromycin 250mg o q24hr 7 days

Response is usually rapid in rickettsial infections

Where does rickettsial disease occur in Australia

Where does rickettsial disease occur in Australia

6 Australian Spotted Fever

Where does rickettsial disease occur in Australia

Where does rickettsial disease occur in Australia

7 SPOTTED FEVER GROUP

TYPHUS GROUP

8 SCRUB TYPHUS GROUP

9 Request for Australian ectoparasites!

Medical doctors and veterinarians. Please send us ectoparasites for analysis: Ticks, fleas, lice, mites

Contact: Dr Stephen Graves Ph: 0407 506 380 (expenses will be reimbursed)

Conclusion

Australia has an almost complete set of rickettsial infections transmitted to human by: • Tick bite (Spotted Fever Group rickettsia) • Mite bite (scrub typhus) • Flea bite (murine typhus or cat flea typhus) • Inhaled infected flea faeces (murine typhus or cat flea typhus)

Conclusion (cont.)

• Other rickettsial infections occur in returned travellers, especially R. africae (African Tick Bite Fever). • Doctors must think of rickettsial diagnosis in the differential. • Clinical diagnosis alone is difficult. • Laboratory tests (especially serology) are usually very helpful. • Treatment relatively easy usually.

10 Acknowledgements Thanks to my colleagues in the Australian Rickettsial Reference Laboratory • Dr John Stenos • Dr Aminul Islam • Dr Gemma Vincent • Dr Haz Hussain-Yusef • Ms Chelsea Nguyen • Ms Josie Proudlock and many collaborators from Australia and overseas.

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